[Metamizol: current status in Dutch practice]. / Pijnbestrijding met metamizol in de Nederlandse praktijk.

Metamizole is a non-selective NSAID with a strong analgesic and spasmolytic effect. In the late 1970s, metamizole has been withdrawn from the market in many industrialized countries because of an allegedly unacceptable high risk of agranulocytosis. The absolute risk of metamizole-related agranulocytosis is estimated to be less than 1 per million daily doses. The incidence of agranulocytosis may be reduced by short-term use and careful consideration when prescribing to specific patient categories. Metamizole has a relatively favorable safety profile with respect to morbidity and mortality compared to other NSAIDs. In the Netherlands the official registration of metamizole has been limited for years to intravenous and postoperative use. In March 2021, the Dutch Medicine Assessment Board certified one oral formulation of metamizol under strict conditions. The debate about the wider application of (oral) metamizole in the Netherlands should be re-opened.

Peritoneal vasculopathy in the pathophysiology of long-term ultrafiltration failure: A hypothesis based on clinical observations
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Ultrafiltration failure in long-term peritoneal dialysis patients is a well-known and important, but poorly-explained complication of the treatment. Transcapillary ultrafiltration consists mainly of small-pore fluid transport and partly of free-water transport. The former is to a large extent dependent on the hydrostatic pressure gradient and on the number of perfused peritoneal microvessels. Free-water transport depends mainly on the crystalloid osmotic gradient. A longitudinal analysis of peritoneal transport has shown a dramatic decrease of net ultrafiltration and small-pore fluid transport after 4 years of peritoneal dialysis. It will be argued that in contrast to common belief, a decrease of osmotically induced water transport cannot be the major contributor to long-term ultrafiltration failure. By exclusion of potential alternatives, the presence of vasculopathy in the peritoneal microcirculation is the most likely explanation. The resulting narrowing of vascular lumina will decrease the hydrostatic pressure gradient and thereby small-pore fluid transport and net ultrafiltration. Deposition of advanced glycosylation end products in peritoneal vessels may be important in the development of vasculopathy. This hypothesis is supported by morphological and functional results of dialysis with "biocompatible" solutions.
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Patient-reported outcomes (PROs) argue against the limited use of peritoneal dialysis in end-stage renal disease
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AIM: Approximately 40% of dialysis patients are durably treated with peritoneal dialysis (PD) in our teaching hospital. Patients' perspectives were studied by patient-reported outcome measurements (PROMs) to find possible explanations for why the generally-reported decline in the use of PD hardly occurred in our facility. MATERIALS AND METHODS: All 75 prevalent adult dialysis patients hemodialysis (HD) duration 27, PD 16 months) were included. All had received predialysis care and education for > 6 month. Cross-sectional sociodemographic and clinical data, SF-36, KDQOL-SF, and predialysis anxiety/depression scores were collected in February 2016. Differences in PROMs between PD and HD patients were analyzed. RESULTS: Despite more comorbidity in the PD population, generally-used dialysis parameters were adequate and similar between HD (n = 42) and PD (n = 33) patients as was annual mortality. Many factors associated with a predialysis modality choice for PD were absent. A higher anxiety/depression score was found in pre-HD compared to pre-PD patients. PROMs were returned by 97%. PD patients performed better on a number of PROMs than their HD counterparts. CONCLUSION: This single-center cross-section with a modest number of patients but an almost 100% patient response shows that having 40% of patients on PD is possible with excellent results in terms of patient-reported outcomes. A structured patient education with attention to personal needs of patients, an adequate infrastructure for PD, and a dedicated team with ongoing patient support are key factors. Sharing best practices may help to slow down or even reverse the decline of PD, which is a pity both for patients and society.
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The Association Between Glucose Exposure and the Risk of Peritonitis in Peritoneal Dialysis Patients.

UNLABELLED: ♦ BACKGROUND AND OBJECTIVE: Little or no clinical evidence is available on the association between glucose exposure and peritoneal host defense in peritoneal dialysis (PD) patients. The objective of the present study was to quantify the exposure to glucose during the first year on PD and investigate the association with subsequent peritonitis. ♦ METHODS: We analyzed prospectively collected demographic and peritonitis data from incident adult PD patients between 1990 and 2010. For the present study, we conducted a review of both in- and outpatient medical records of all patients to obtain their day-to-day dialysis schemes during the first year on PD. From these data, the average exposure to glucose was quantified. The exposure was stratified into low- and high-glucose groups based on the median, analyzed per standard deviation and in quartiles. Cox proportional hazard models were used to calculate crude and adjusted hazard ratios (HRs) and 95% confidence intervals for the association between glucose exposure and peritonitis. Adjustments were made for age, sex, primary kidney disease, diabetes mellitus, Davies comorbidity score and the treatment period. ♦ RESULTS: In total, 230 patients were included in the study of whom 151 (66%) experienced a first peritonitis episode. The median follow-up time was 2.6 years (interquartile range [IQR]: 1.9 - 3.8) in the low-glucose group and 3.1 (IQR: 2.1 - 4.2) in the high-glucose group. After adjustment for confounding factors, no association between high glucose exposure and the risk of peritonitis was found (HR: 0.81; 0.55 - 1.17). No association was present when glucose exposure was analyzed per standard deviation (SD) (HR: 0.98; 0.79 - 1.21) or patient quartiles were applied. No association was identified between glucose exposure and severe peritonitis, Staphylococcus aureus peritonitis, or a peritonitis episode that lasted more than 14 days. ♦ CONCLUSIONS: Exposure to glucose is not associated with an increased risk of peritonitis. The equilibrium between glycemic harm to peritoneal host defense and detrimental effects of glucose on invading microorganisms may determine the susceptibility to peritoneal infection.

The Mutual Relationship Between Peritonitis and Peritoneal Transport.

UNLABELLED: ♦ BACKGROUND: Preservation of the peritoneum is required for long-term peritoneal dialysis (PD). We investigated the effect of multiple peritonitis episodes on peritoneal transport. ♦ METHODS: Prospectively collected data from 479 incident PD patients treated between 1990 and 2010 were analyzed, using strict inclusion criteria: follow-up of at least 3 years with the availability of a Standard Peritoneal Permeability Analysis (SPA) in the first year after start of PD and within the third year of PD, without peritonitis preceding the first SPA. For the purpose of the study, we only included patients who remained peritonitis-free (n = 28) or who experienced 3 or more peritonitis episodes (n = 16). ♦ RESULTS: At baseline the groups were similar with regard to small solute and fluid transport. However, the frequent peritonitis group had lower peritoneal protein clearances compared to the no peritonitis group, resulting in lower dialysate concentrations of proteins: albumin 196.5 mg/L vs 372.5 mg/L, IgG 36.4 mg/L vs 65.0 mg/L, and α-2-macroglobulin (A2M) 1.9 mg/L vs 3.6 mg/L, p <0.01. No differences in serum concentrations were present. A comparison between the transport slopes over time in both groups showed a positive time trend of mass transfer area coefficient (MTAC) creatinine (p = 0.03) and glucose absorption (p = 0.09) and a negative trend of transcapillary ultrafiltration (p = 0.06), when compared to the no peritonitis group. Frequent peritonitis did not affect free water transport. ♦ CONCLUSIONS: Slow initial peritoneal transport rates of serum proteins result in lower dialysate concentrations, and likely a lower opsonic activity, which is a risk factor for peritonitis. Patients with frequent peritonitis show an increase in small solute transport and a concomitant decrease of ultrafiltration. In long-term peritonitis-free PD patients, small solute transport decreased, while ultrafiltration increased. This suggests that frequent peritonitis leads to an increase of the vascular peritoneal surface area without all the structural membrane alterations that may develop after long-term PD.

The first peritonitis episode alters the natural course of peritoneal membrane characteristics in peritoneal dialysis patients.

OBJECTIVE: Little or no evidence is available on the impact of the first peritonitis episode on peritoneal transport characteristics. The objective of this study was to investigate the importance of the very first peritonitis episode and distinguish its effect from the natural course by comparison of peritoneal transport before and after infection. PARTICIPANTS: We analyzed prospectively collected data from 541 incident peritoneal dialysis (PD) patients, aged > 18 years, between 1990 and 2010. Standard Peritoneal Permeability Analyses (SPA) within the year before and within the year after (but not within 30 days) the first peritonitis were compared. In a control group without peritonitis, SPAs within the first and second year of PD were compared. MAIN OUTCOME MEASUREMENTS: SPA data included the mass transfer area coefficient of creatinine, glucose absorption and peritoneal clearances of ß-2-microglobulin (b2m), albumin, IgG and α-2-macroglobulin (a2m). From these clearances, the restriction coefficient to macromolecules (RC) was calculated. Also, parameters of fluid transport were determined: transcapillary ultrafiltration rate (TCUFR), lymphatic absorption (ELAR), and free water transport. Crude and adjusted linear mixed models were used to compare the slopes of peritoneal transport parameters in the peritonitis group to the control group. Adjustments were made for age, sex and diabetes. RESULTS: Of 541 patients, 367 experienced a first peritonitis episode within a median time of 12 months after the start of PD. Of these, 92 peritonitis episodes were preceded and followed by a SPA within one year. Forty-five patients without peritonitis were included in the control group. Logistic reasons (peritonitis group: 48% vs control group: 83%) and switch to hemodialysis (peritonitis group: 22% vs control group: 3%) were the main causes of missing SPA data post-peritonitis and post-control. When comparing the slopes of peritoneal transport parameters in the peritonitis group and the control group, a first peritonitis episode was associated with faster small solute transport (glucose absorption, p = 0.03) and a concomitant lower TCUFR (p = 0.03). In addition, a discreet decrease in macromolecular transport was seen in the peritonitis group: mean difference in post- and pre-peritonitis values: IgG: -8 µL/min (p = 0.01), a2m: -4 µL/min (p = 0.02), albumin: -10 µL/min (p = 0.04). Accordingly, the RC to macromolecules increased after peritonitis: 0.09, p = 0.04. CONCLUSIONS: The very first peritonitis episode alters the natural course of peritoneal membrane characteristics. The most likely explanation might be that cured peritoneal infection later causes long-lasting alterations in peritoneal transport state.

Erythropoiesis-stimulating agents and thrombotic events in dialysis patients.

BACKGROUND: Erythropoiesis-stimulating agents (ESA) have been associated with a higher cardiovascular event and mortality rate in dialysis patients. The ESA-associated risk of arterial thrombotic events is mainly based on composite endpoints of anemia-correction trials targeting high hemoglobin levels. The ESA-associated risk of venous thromboembolism (VTE) has not been studied in dialysis patients yet. We therefore aimed to determine the association between ESA use and dose with ischemic stroke, myocardial infarction (MI) and VTE. MATERIALS AND METHODS: In NECOSAD, a Dutch cohort study of incident dialysis patients, data on ESA use and dose, comorbidities and laboratory parameters were routinely collected every 6 months. Thrombotic events were collected by chart review of all dialysis patients from 6 participating centers. Time-dependent Cox regression analysis was performed to calculate hazard ratios (HR) with 95% confidence interval (CI) for ischemic stroke, MI and VTE with updated information on ESA use and dose. RESULTS: Patients with ESA had a 2 times lower ischemic stroke rate than patients without ESA: adjusted HR 0.45 (95% CI 0.23-0.90), and an adjusted HR of 1.12 (95% CI 0.58-2.14) for MI. No evident ESA dose response effect was present. Unadjusted HR for VTE was 0.41 (95% CI 0.11-1.50) for patients with ESA compared to patients without, but the low event rate made further adjustments impossible. CONCLUSIONS: In our observational cohort of dialysis patients, reflecting everyday clinical practice, ESA was not associated with an excess of thrombotic events. Further investigation is needed to enlighten the true cause of ESA-associated cardiovascular events and mortality.

The association between dialysis modality and the risk for dialysis technique and non-dialysis technique-related infections.

BACKGROUND: Infections are a major cause of morbidity and mortality among dialysis patients. Dialysis modality has been hypothesized to be a potential immunomodulatory factor. The objective of this study was to determine the influence of the first dialysis modality on the risk for infections on dialysis. METHODS: Our study was conducted utilizing the Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) cohort of incident dialysis patients. Medical records of all patients from two tertiary care university hospitals and three regional hospitals were reviewed using pre-specified criteria. Information about infections was collected from the start of dialysis until death, modality switch, study withdrawal, kidney transplantation or at the end of the study. Age-standardized incidence rates for infections were calculated. Poisson regression analysis was used to calculate adjusted incidence rate ratios (IRRs). RESULTS: In total, 452 patients, of whom 285 started with haemodialysis (HD) and 167 with peritoneal dialysis (PD), were included. The median follow-up time on the first dialysis modality was similar for HD and PD, 1.8 and 2.0 dialysis years, respectively. During the first 6 months, the age-standardized infection incidence rate was higher on HD compared with PD patients (P = 0.02). Overall, PD patients had a higher infection risk [adjusted IRR: 1.65, 95% confidence interval (CI): 1.34-2.03], which could be attributed to a 4-fold increased risk for dialysis technique-related infections. The risk for non-dialysis technique-related infections was lower in PD patients (adjusted IRR: 0.56, 95% CI: 0.40-0.79). CONCLUSIONS: Overall, PD patients carry a higher risk for infections. Interestingly, the risk for non-dialysis technique-related infections was higher in HD patients. The links between dialysis modality and the immune system are expected to explain this difference, but future studies are needed to test these assumptions.

A qualitative systematic review of the literature supporting a causal relationship between exit-site infection and subsequent peritonitis in patients with end-stage renal disease treated with peritoneal dialysis.

OBJECTIVE: The objective of our research was to summarize and review evidence supporting a causal relationship between exit-site infection and peritonitis in peritoneal dialysis (PD) patients. DATA SOURCES: We undertook a qualitative review of studies retrieved from MEDLINE, EMBASE, and PubMed, and supplemented that process with a hand search of references and abstracts in the literature. STUDY SELECTION: Our quality criteria were based on the Paediatric Risk of Mortality guidelines, definitions, and recommendations from the International Society for Peritoneal Dialysis (ISPD), and the Bradford Hill criteria for causality. All identified abstracts were reviewed for content. Of 776 abstracts, 59 were selected for full-text evaluation, and 22 of those met the ISPD criteria for good-quality research in PD-related infections. Of the 22 eligible studies, 9 met the study's quality criteria and were included in the summative analysis. No articles reported sufficient data for a quantitative analysis. DATA EXTRACTION: Information on study design, study population characteristics, definitions, peritonitis rates, exit-site care protocol, exit-site treatment protocol, follow-up period, potential bias, and outcomes was extracted. Criteria for including data in the final study were determined using ISPD guidelines. DATA SYNTHESIS: Of the 9 included studies, 8 suggested that a history of exit-site infection increased the risk for subsequent peritonitis. Of those studies, 3 met 5 causality criteria, 4 met 4 causality criteria, and 1 met 3 causality criteria. CONCLUSIONS: The literature provides weak evidence to support a causal relationship between exit-site infection and subsequent peritonitis. Few criteria for causation were met. We were unable to attribute causation and could assume an association only. The exclusion of studies focusing on PD-related tunnel infections may be viewed as both a strength and a limitation of the present work.

The association between exit site infection and subsequent peritonitis among peritoneal dialysis patients.

BACKGROUND AND OBJECTIVES: Peritonitis is the most common infectious complication seen in peritoneal dialysis (PD). Traditionally, exit site infection (ESI) has been thought to predispose PD patients to peritonitis, although the risks have not been quantified. This study aimed to quantify the risk of PD peritonitis after ESI. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from 203 clinically stable PD patients >18 years of age who were followed as part of a randomized controlled trial over 18 months were used to estimate the risk of developing peritonitis within 30 days of an ESI compared with individuals who did not have a recent ESI. Sensitivity analyses were performed at 15, 45, and 60 days. RESULTS: Patients were mostly male (64.5%) and Caucasian, with a mean age of 60.5 ± 14.4 years. There were 44 ESIs and 87 peritonitis episodes during the 18-month study. Seven patients had an ESI followed by peritonitis within 30 days. Using a frailty model, patients who had an ESI had a significantly higher risk of developing peritonitis within 30 days, even if the ESI was appropriately treated. This risk was maximal early on and diminished with time, with hazard ratios (95% confidence interval) of 11.1 at 15 days (HR=11.1, 95% CI=4.9-25.1), 5.3 at 45 days (2.5-11.3), and 4.9 at 60 days (2.4-9.9). In 2.3% of patients, subsequent peritonitis was caused by the same organism as the previous ESI. CONCLUSIONS: A strong association between a treated ESI and subsequent PD peritonitis was present up to 60 days after initial diagnosis.